The fate of cell survival or death is a tightly regulated. Apoptosis, one of the major cell death mechanisms, is defective in many cancers. Apoptosis occurs in small fraction of cells within the irradiated solid tumors. Autophagy, a highly conserved self-elimination mechanism that utilizes lysosome/vacuoles for cellular degradation is a backup cell death pathway when apoptosis is blocked. Our preliminary data support the hypothesis that autophagy is an important alternative cell death mechanism in tumor cells exposed to ionizing radiation when the apoptotic pathway is blocked. In the absence of pro-apoptotic proteins, Bak/Bax or caspase 3/7, we found that autophagy is upregulated and occurred in over 50% of irradiated cells. As a consequence, we found that up-regulation autophagy confers increased radiation sensitivity of cancer cells. Central to this hypothesis is the concept that Bak/Bax or caspase 3/7 negatively regulate autophagy, upon radiation-induced stress and that autophagy is enhanced in cells lacking these pro-apoptotic proteins. We believe that induction of autophagy through 1) direct activation of autophagic signaling by mTOR inhibitors or overexpression of autophagic proteins;or 2) inhibition of Bak/Bax or caspase 3/7, will enhance the biological effects of radiation in cancer models. Three specific aims are proposed to test this hypothesis. Specific Aim 1 will identify mechanisms by which Bak/Bax or caspase 3/7 regulate radiation-induced autophagy. Specific Aim 2 will determine whether inhibition of Bak/Bax or caspase 3/7, induction of the autophagic pathway, and enhanced radiosensitization is a global response in cancer cells. Specific Aim 3 will determine whether induction of autophagic signaling by inhibition of mTOR or over expression of autophagic proteins enhances radiation response. The proposed study is to understand the molecular interaction between apoptosis and autophagy during radiation-induced stress and to identify novel targets for enhancing radiotherapy in cancer models. The significance of this study is to expand our understanding of the complex molecular signaling, which determines the fate of irradiated cells. This knowledge will be explored to improve the efficacy of conventional radiotherapy that is being used for cancer patients.